Adrienne M. Hammill

Sirolimus for the treatment of complicated vascular anomalies in children.

Vascular anomalies comprise a diverse group of diagnoses. While infantile hemangiomas are common, the majority of these conditions are quite rare and have not been widely studied. Some of these lesions, though benign, can impair vital structures, be deforming, or even become life‐threatening. Vascular tumors such as kaposiform hemangioendotheliomas (KHE) and complicated vascular malformations have proven particularly difficult to treat.

Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies.

BACKGROUND AND OBJECTIVES: Complicated vascular anomalies have limited therapeutic options and cause significant morbidity and mortality. This Phase II trial enrolled patients with complicated vascular anomalies to determine the efficacy and safety of treatment with sirolimus for 12 courses; each course was defined as 28 days. METHODS: Treatment consisted of a continuous dosing schedule of oral sirolimus starting at 0.8 mg/m2 per dose twice daily, with pharmacokinetic-guided target serum trough levels of 10 to 15 ng/mL. The primary outcomes were responsiveness to sirolimus by the end of course 6 (evaluated according to functional impairment score, quality of life, and radiologic assessment) and the incidence of toxicities and/or infection-related deaths. RESULTS: Sixty-one patients were enrolled; 57 patients were evaluable for efficacy at the end of course 6, and 53 were evaluable at the end of course 12. No patient had a complete response at the end of course 6 or 12 as anticipated. At the end of course 6, a total of 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. Two patients were taken off of study medicine secondary to persistent adverse effects. Grade 3 and higher toxicities attributable to sirolimus included blood/bone marrow toxicity in 27% of patients, gastrointestinal toxicity in 3%, and metabolic/laboratory toxicity in 3%. No toxicity-related deaths occurred. CONCLUSIONS: Sirolimus was efficacious and well tolerated in these study patients with complicated vascular anomalies. Clinical activity was reported in the majority of the disorders.

Oncolytic virotherapy reaches adolescence.

Lytic viruses kill cells as a consequence of their normal replication life cycle. The idea of harnessing viruses to kill cancer cells arose over a century ago, before viruses were even discovered, from medical case reports of infections associated with cancer remissions. Since then, there has been no shortage of hype, hope, or fear regarding the prospect of oncolytic virotherapy for cancer. Early developments in the field included encouraging antitumor efficacy both in animal studies in the 1920s–1940s and in human clinical trials in the 1950s–1970s. Despite its long‐standing history, oncolytic virotherapy was an idea ahead of its time. Without needed advances in molecular biology, virology, immunology, and clinical research ethics, early clinical trials resulted in infectious complications and were fraught with controversial research conduct, so that enthusiasm in the medical community waned. Oncolytic virotherapy is now experiencing a major growth spurt, having sustained numerous laboratory advances and undergone multiple encouraging adult clinical trials, and is now witnessing the emergence of pediatric trials. Here we review the history and salient biology of the field, including preclinical and clinical data, with a special emphasis on those agents now being tested in pediatric cancer patients. Pediatr Blood Cancer. 2010;55:1253–1263.

Malignant transformation of infantile hemangioma to angiosarcoma: Response to chemotherapy with bevacizumab

We describe a child initially diagnosed with multi‐focal infantile hemangioma (cutaneous, hepatic, pulmonary), a benign vascular lesion, which underwent malignant transformation to angiosarcoma. The use of anti‐angiogenic agents, such as bevacizumab, an anti‐vascular endothelial growth factor (VEGF) antibody, has been reported in adults with angiosarcoma. Treatment with chemotherapy (gemcitabine and docetaxel) and bevacizumab resulted in disease response with progression free survival of 12 months. This report describes the response to chemotherapy and bevacizumab in a child with angiosarcoma and highlights the potential for malignant transformation of benign vascular lesions and the need for careful monitoring. Pediatr Blood Cancer 2014;61:2115–2117.

Response of Blue Rubber Bleb Nevus Syndrome to Sirolimus Treatment.

Blue rubber bleb nevus syndrome (BRBNS) is a rare multifocal venous malformation syndrome involving predominantly the skin and gastrointestinal tract. Traditional treatment modalities include corticosteroids, interferon‐α, sclerotherapy, and aggressive surgical resection. Sirolimus has been used in several single case reports.

Other vascular tumors

Vascular tumors are rare in children and adults. Classification of these tumors has been difficult, especially in the pediatric population, due to the rarity of these lesions, the unusual morphologic appearance, their diverse clinical behavior, and no independent stratification for pediatric tumors. In 2013, The World Health Organization updated the classification of soft tissue vascular tumors. Pediatric tumors were not independently stratified and the terminology was mostly left unchanged, but the intermediate category of tumors was divided into locally aggressive and rarely metastasizing. These tumors are treated with multimodality therapy and therefore need the guidance of an interdisciplinary team for best care.

Skin imaging modalities quantify progression and stage of infantile haemangiomas

DEAR EDITOR, Infantile haemangiomas (IH) are deep, superficial or mixed vascular neoplasms with rapidly proliferating endothelial cells that stabilize and involute with diminishing cellular activity, apoptosis and resolution over 7–10 years. Clinicians evaluate progression, treatment response and stage by inspection, photography (colour, size, shape) and palpation (temperature, deformability). Lightening, flattening, reduced temperature and softness signal involution. The limitations of subjective methods and need for objective metrics are recognized. Colour, infrared (IR) and three-dimensional (3D) imaging have been applied to IHs. Photographs are compared for improvement as stable/worse (0%), slight (< 25%), moderate (25–50%), good (50–75%) and excellent (> 75%) using the Visual Analog Scale. However, images may be nonstandardized (position, lighting) and results subjective as improvement criteria may be inconsistently applied. IR surface intensity and distribution are affected by tumour depth, size, metabolism, vasculature and perfusion. Dynamic IR applies a temperature stress and the rewarming pattern provides physiological information. We conducted a prospective observational proof of concept study to determine the utility of standardized skin imaging of colour, IR thermography and 3D shape for quantifying IH progression [Clinical Trial Registration: www.clinicaltrials.gov (Identifier NCT02061735)]. We compared these measurements to clinical stage (proliferating, stable, involuting). Data were stratified by age at evaluation, i.e. 1–2, 3–5, 6–9, 10–19 and ≥ 19 months corresponding to expected growth. Fifty-nine patients with 67 superficial or mixed IHs and at least two visits yielded 250 evaluations over 18 months. Deep IHs were excluded due to the small number. Clinicians from our multidisciplinary Hemangioma and Vascular Malformation Center decided the treatment: propranolol (1–2 mg kg 1 daily), topical timolol (one drop 0 5% gel twice daily) or no treatment, and assessed patients in person. The Institutional Review Board approved the research and parents/guardians provided written informed consent. Standardized colour, IR and 3D images of the IH and contralateral controls were taken (Nikon D90 camera, 60-mm lens, 12 3 megapixels, cross polarization, wireless flash; Nikon Corporation, Tokyo, Japan; FLIR T400 IR camera; FLIR Inc., Wilsonville, OR, U.S.A.; 3D scanner; Artec MHT, Artec Group, San Diego, CA, U.S.A., respectively). IR responses to 30-s cooling (18 0 2 °C, Jack Frost; Cardinal Health, McGaw Park, IL, U.S.A.) and rewarming (30 s) were quantified for a subset of evaluations. Photographs were colour corrected, separated into L*, a* and b* images (ImageJ; NIH, Washington, DC, U.S.A.), coregistered with IR images and analysed with a graphical interface employing landmark-based registration and algorithms (MATLAB ; MathWorks, Natick, MA, U.S.A.). Thresholds were applied to identify features of the IH only. Colour and IR intensities and areas were described as means and number of pixels above threshold, respectively. The highest 10% of pixels isolated the IH highest activity for dynamic IR with behaviour measured as area under the curves [AUCcooling (cool), AUCrewarming (rw)]. Height and volume were determined from 3D scans (3dMD Vultus; 3dMD, Atlanta, GA, U.S.A.). Outcomes by time and stage were analysed using univariate general linear models with treatment and depth (time) and age and treatment (stage) as covariates, post-hoc least significant difference for pairwise comparisons (P < 0 05) (SPSS; IBM, Armonk, NY, U.S.A.). Means were 7 4 months, 8 4 months in study, 3 8 evaluations and 3 months between evaluations. Fifty IHs were treated and 51 were mixed. Clinical stage discrepancies were resolved by consensus. Figure 1 shows IH progression for one subject. Lightness intensity and height were the most discriminating outcomes. Lightness increased and height decreased over time (P < 0 05) (Fig. 2a,b; see also Supporting Information). Red intensity was highest at 2 2 and 4 5 months, decreasing by 8 0 months (P < 0 05). IR intensity was higher for 2 2 and 4 5 vs. 12 8 and 27 7 months (P < 0 05) (Fig. 2b). Changes followed a logarithmic pattern. AUCcool AUCrw differences (dynamic IR) were 1 5 6 2, 17 4 3 6, 34 6 5 3, 28 4 5 5 and 20 6 7 3 for 2 2, 4 5, 8 0, 12 8 and 27 7 months, respectively. The smaller difference for 2 2 vs. all other months (P < 0 05) indicates faster recovery. AUCrw was 1109 23, 1054 12, 1009 12, 1004 18 and 1000 24, respectively and greater at 2 2 months (P < 0 05), indicating faster rewarming. The IR area consistently extended beyond the visual IH boundaries (mean visible : IR ratio of 33 18%), suggesting that a third to a half of potentially relevant information is not visible. The IR maps (Fig. 1) show the regions of greatest thermal activity. The results are consistent with the expected changes as higher proangiogenic factors during proliferation cause increased microcirculation followed by vasoconstriction

Developmental pharmacokinetics of sirolimus: Implications for precision dosing in neonates and infants with complicated vascular anomalies

Sirolimus has recently been shown to be efficacious and tolerable in pediatric patients with complicated vascular anomalies. Nevertheless, dosing information remains very limited especially for neonates and infants. The purpose of this study was to develop an age‐appropriate sirolimus starting dosing regimen based on the developmental changes in drug elimination capacity using data collected in neonates and infants.

Leveraging a Sturge-Weber Gene Discovery: An Agenda for Future Research

Sturge-Weber syndrome (SWS) is a vascular neurocutaneous disorder that results from a somatic mosaic mutation in GNAQ, which is also responsible for isolated port-wine birthmarks. Infants with SWS are born with a cutaneous capillary malformation (port-wine birthmark) of the forehead or upper eyelid which can signal an increased risk of brain and/or eye involvement prior to the onset of specific symptoms. This symptom-free interval represents a time when a targeted intervention could help to minimize the neurological and ophthalmologic manifestations of the disorder. This paper summarizes a 2015 SWS workshop in Bethesda, Maryland that was sponsored by the National Institutes of Health. Meeting attendees included a diverse group of clinical and translational researchers with a goal of establishing research priorities for the next few years. The initial portion of the meeting included a thorough review of the recent genetic discovery and what is known of the pathogenesis of SWS. Breakout sessions related to neurology, dermatology, and ophthalmology aimed to establish SWS research priorities in each field. Key priorities for future development include the need for clinical consensus guidelines, further work to develop a clinical trial network, improvement of tissue banking for research purposes, and the need for multiple animal and cell culture models of SWS.

Infantile hemangioma status by dynamic infrared thermography: A preliminary study.

Infantile hemangiomas (IH) are initially warm due to increased proliferation and perfusion then involute with apoptosis and reduced perfusion. Objective quantitative evaluation of IH treatment response is essential for improving outcomes. We applied a functional imaging method, dynamic infrared (IR) thermography, to investigate IH status versus control skin and over time.